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48 Cards in this Set
- Front
- Back
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Nicotinic Receptor |
(Ligand gated ion channel) NNautonomic ganglia (SNS and PNS)and adrenal medulla NMneuromuscular junction (skeletal muscle) |
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MUSCARINIC |
(G-protein-coupled receptor) M1: autonomic ganglia, parietal nerves M2: heart, presynaptic neurons M3: glands, endothelium, smooth muscle
M4 & M5: Not highly expressed in ANS M1, M3, & M5: excitatory response M2 & M4: inhibitory response |
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Sympathetic Nervous System |
• Preganglionic cell bodies originate in thoracic and lumbar spinal cord. • Sympathetic ganglion synapse uses Ach as a neurotransmitter. While the postganglionic neuron synapses uses Norepinephrine. • Exception- Postganglionic neurons innervating sweat glands uses Ach. • SNS usually stimulatory (fight or flight response) |
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Parasympathetic Nervous system |
• Preganglionic cell bodiesoriginate in sacral region of spinal cord and in the medulla. • Parasympathetic pre-ganglionic and post ganglionic synapse uses Ach as a neurotransmitter. • PsNS usually inhibitory (Rest and Digest responses- body maintenance, conservation of energy etc.) |
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PNS / Muscarinic Agonists Effects |
– classic PNS actions (Parasympathomimetics) • slowing of heart • smooth muscle contraction • glandular secretion |
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PNS / Muscarinic Agonists Side Effects |
Memory booster: Too much cholinergic stimulation. There are some useful mnemonics that can aid yourrecognition of cholinergic overdose or excessive cholinergic nerve activity:
1) SLUG-BAM: salivation, sweating, lacrimation, urination, GI upset, bradycardia,bronchoconstriction, bronchorrhea, abdominal cramps, miosis
2) SLUD-B: salivation, sweating, lacrimation, urination, defecation, bradycardia,bronchoconstriction, bronchorrhea
3) SLUDGE-BBB: salivation, lacrimation, urination, defecation, GI upset, emesis,bronchorrhea, bronchospasm, bradycardia 4) DUMBELS: diarrhea, diaphoresis, urination, miosis, bronchorrhea, bronchospasm,bradycardia, emesis, lacrimation, salivation |
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CARDIAC INHIBITION |
Vagal stimulation or agonist administrationstimulates M2 receptors produce: 1) Negative chronotropic effectdecreased rate of spontaneous depolarization (K channels open)slower pacemaker currentslower AV conduction 2) Negative inotropic effectM2 stimulation lowers cAMPeffect more prominent in atria |
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VASCULAR INHIBITION / EXCITATION |
Dual effect mediated by M3 receptors on endothelium or VSM. 1) Endothelium-dependent (NO) vasodilation 2) Direct contraction of VSM |
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Acetylcholine |
• Very limited clinical use – widespread action; potential side effects • MAChR and NAChR – ultra-short half-life • AChE • Pseudo-ChE • Ophthalmic surgery – 1% solution produces miosis (pupil constriction) (MIOCHOL) |
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METHACHOLINE |
MAChR Agonist • Limited clinical use – somewhat longer half-life compared to ACh• Diagnosis of bronchial airway hyperreactivity – PROVOCHOLINE (can “provoke” constriction) – low-dose inhalation: • no effect in normal patients • asthmatic patients hypersensitive to methacholine challenge |
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BETHANACHOL |
MAChR Agonist • More selective for MAChR • Resistant to hydrolysis by AChE – longer half-life • Primary use: smooth muscle contraction – stimulate G.I. propulsion • postoperative G.I. atony • congenital megacolon – stimulate bladder emptying • postoperative urinary retention • spinal injury (detrusor muscle contra) • non-obstructive |
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PILOCARPINE |
MAChR Agonist • More selective for MAChR • Resistant to hydrolysis by AChE – longer half-life (but less potent natural alkaloid) • Glaucoma – contract ciliary muscle – increase flow of aqueous humor • Xerostomia – powerful stimulation of salivary glands • head/neck radiation, surgery, Sjogren’s syndrome • Diaphoresis (excessive sweating) • Tertiary (uncharged) amine: CNS effects |
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CARBACHOL |
• Non-selective (more NAChR) • Resistant to hydrolysis by AChE – longer half-life • Ganglionic stimulation (NAChR) – limits clinical use • Glaucoma – miosis |
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“Indirect-Acting” Cholinergic Agonists |
• Agents that do not stimulate receptors,but rather, enhance the effects of ACh. • By inhibiting AChE, these agents prolongand intensify the effects of ACh. • There are 2 categories of AChE Inhibitors: – Reversible (“stigmines”) – Irreversible (OP toxins) |
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Reversible AChE-Inhibitors |
• Enhance contraction of smooth muscle – G.I. (especially colon) – urinary tract • Glaucoma – miosis • Myasthenia gravis – AChE-I increase ACh levels at NMJ – Improve strength and function – No cure, but… – Effective treatment • Reversal of NM blockade (e.g., anesthesia) – AChE-I can reverse competitive NM block due toantagonism of NAChR’s. • Alzheimer’s Disease – long-acting AChE-Inhibitors |
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NEOSTIGMINE |
• Quaternary amine – little CNS action • Smooth muscle contraction – G.I. atony, postoperative paralytic ileus, colon – atony of detrussor muscle, postoperativedysuria • Glaucoma • Myasthenia gravis • Reverse neuromuscular blockers |
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PYRIDOSTIGMINE |
• Quaternary amine – little CNS action • Similar to Neostigmine – longer duration of action • Most common treatment for MG in U.S. |
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PHYSOSTIGMINE |
• Tertiary amine – can cross into CNS – treat CNS effects of anticholinergic overdose • atropine • antipsychotics • some antidepressants |
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EDROPHONIUM |
• Quaternary amine alcohol – rapid onset – short duration of action (10-20 minute) • Diagnosis of MG (“Tensilon Test”) – i.v. injection briefly improves muscle strength inpatients with MG |
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Longer-Acting AChE-Inhibitors |
• TACRINE (Cognex) DONEPEZIL (Aricept) RIVASTIGMINE (Exelon) GALANTAMINE (Reminyl) – longer duration of action – slow progressive dementia of Alzheimer’s |
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IRREVERSIBLE AChE-Inhibitors |
• Bind to and inactivate AChE – Organophosphorous pesticides & nerve gases – strong, covalent phosphorylation – “aging” makes AChE irreversible • Pralidoxime (2-PAM) can reactivate AChE • must be given before aging of enzyme • Little clinical application (too toxic) – see box in lecture notes • ECHOTHIOPHATE – Quaternary amine: does not penetrate skin – Glaucoma: produces powerful, persistent miosis |
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Muscarinic Antagonists |
• Block the effects of ACh at MAChR’s. • Main “parasympatholytic” actions: – cardiac stimulation – inhibition of smooth muscle function – inhibition of gland function • Effects are dose-dependent • None are completely “selective” – Most will block M1 – M5 |
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ATROPINE |
Belladonna Alkaloid • Antimuscarinic actions – inhibits classic PNS effects – too powerful for general use • Dose-dependent effects |
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ATROPINE: clinical use on Eye |
– mydriasis (retinal exams) – glaucoma! – cycloplegia (accurate measure of refraction) – promotes dry eye |
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ATROPINE: clinical use on Respiratory Tract |
-promotes bronchial dilation – dries secretions (surgical pre-op med) – impairs bronchociliary activity (limits use) |
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ATROPINE: clinical use on Heart |
– tachycardia (following slight bradycardia) – treat post-MI bradycardia – enhanced conduction (treat AV block) |
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ATROPINE: clinical use on GI |
– antispasmotic effect (side effects limit use) – treat irritable bowel |
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ATROPINE: clinical use on Urinary Tract |
– decrease contractile tone, amplitude, frequency – other agents are preferred for O.B. |
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ATROPINE: clinical use on DUMBELS "cholinergic crisis" |
– insecticide (OP AChE-I) poisoning – mushroom poisoning (“muscarine”) – WMD / terrorist attack (sarin- nerve gas) – also used to alleviate excessive “stigmine”effects during treatment for MG |
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SCOPOLAMINE |
Belladonna Alkaloid • Peripheral effects: – similar to atropine • Central effects: – depression & amnesia – motion sickness (prophylactic) – transdermal patch (72 hours) – Parkinsonism (before levodopa) |
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IPRATROPIUM |
• Isopropyl-atropine – similar to atropine • Asthma / COPD – inhalation administration – fewer systemic side effects – bronchodilation – does not inhibit mucociliary clearance – Treatment of Rhinorrhea- running nose |
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TIOTROPIUM |
• Similar to ipratropium • More “bronchoselective”? – less affinity for M2 receptors • Primary use: COPD – inhalation administration (dry powder) – does not inhibit mucociliary clearance – longer duration of action – once-a-day dosing |
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PIRENZEPINE |
• More selective for the M1 receptor – less potential side effects • Peptic ulcer – decreased acid secretion – parietal cells express M1 receptors – M1 receptors on PNS ganglia – largely replaced by H2 blockers / Proton Pump Inhibitors |
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“M3 antagonists” for Overactive Bladder |
• TOLTERODINE (DETROL) • OXYBUTYNIN (DITROPAN) • DARIFENACIN (ENABLEX) • SOLIFENACIN (VESICARE) • More selective for the M3 receptor – less potential side effects – overactive bladder – urinary incontinence |
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NICOTINE |
Nicotinic Receptor Agonist • activates NN and NM receptors – first stimulates – then depresses (desensitizes) activity • no therapeutic uses • Used in smoking cessation – gum (NICORETTE), patch (NICODERM), ornasal spray (NICOTROL) VARENICLINE (Chantix): partial agonistat CNS NAChR reduces nicotine craving |
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Nicotinic Receptor Antagonists |
• NN receptor antagonists – ganglionic blocking agents • NM receptor antagonists – neuromuscular blocking agents |
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Ganglionic (NN receptor) Blockers |
• Block ganglia in the PNS and SNS • Responses are too complex andunpredictable for general use • MECAMYLAMINE – approved ganglionic blocker – competitive blockade at NN receptor – lowers blood pressure |
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Neuromuscular Blocking Agents |
Primary use: Surgery (muscle relaxants) |
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Non-Depolarizing Blockers |
• Competitive antagonists at NM • d-TUBOCURARINE –derived from CURARE –some inhibition of NN receptors –histamine release- causebronchospasm –rarely used to day |
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DOXACURIUM |
• More selective for NM receptor • Less histamine release • Longer duration of action |
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ROCURONIUM |
• Least potent • Given in higher doses • Rapid onset of action • Little histamine release |
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ATRACURIUM |
• CISATRACURIUM • Intermediate duration of action • Little histamine release • No renal / hepatic metabolism –ideal for patients with kidney / liverdisease |
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MIVACURIUM |
• Hydrolyzed bypseudocholinesterase • Short duration of action • Watch for patients geneticallydeficient in ChE! • Some histamine release |
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SUCCINYLCHOLINE |
Depolarizing Blocker • Initial depolarization • Depolarized block • Very rapid onset (30 sec) • Very short duration (3-5 minutes) • Metabolized by pseudo-ChE, notAChE |
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SUCCINYLCHOLINE Side Effects |
• Hyperkalemia –releases intracellular K –problem in burn patients –can result in arrhythmias • Myalgia –soreness (after contraction) • May stimulate ganglia (NN) • Malignant Hyperthermia –combination with some generalanesthetics –muscle rigidity & heat production –calcium release from SR –Treatment • DANTROLENE • cooling |
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DIAZEPAM |
Skeletal MuscleRelaxant -Stimulates GABA-A receptorsto inhibit synaptictransmission in spinal cord toreduce muscle tone. |
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BACLOFEN |
Skeletal Muscle Relaxant -Stimulates GABA-B receptorsto reduce release of excitatoryamino acids in brain and spinalcord to reduce musclespasticity. |
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DANTROLENE |
Skeletal Muscle Relaxant -Inhibits calcium release fromsarcoplasmic reticulum toinhibit excitation-contractioncoupling in skeletal muscle. |
